Effect of pueraria on left ventricular remodelling in HFrEF: A systematic review and meta-analysis

Background Heart failure with reduced ejection fraction (HFrEF) is a prevalent cardiovascular disease globally, posing a significant burden on healthcare and society. Left ventricular remodelling is the primary pathology responsible for HFrEF development and progression, leading to increased morbidity and mortality. Pueraria, a traditional Chinese herbal medicine and food, is commonly used in China to treat HFrEF. Accumulating evidence suggests that pueraria can effectively reverse left ventricular remodelling in HFrEF patients. This meta-analysis aims to assess the impact of pueraria on left ventricular remodelling in HFrEF patients. Methods Eight electronic databases, including PubMed, EMBASE, Clinicaltrials.gov, Cochrane Library, Wanfang, CNKI, CQVIP, and CBM were searched for literature from inception to June 2023. All randomized controlled trials (RCTs) using pueraria in the treatment of HFrEF were included. The Cochrane Risk of Bias tool was utilized for RCTs’ methodological evaluation, while Review Manager 5.4.1 was used to analyze the data. Results Nineteen RCTs with a total of 1,911 patients (1,077 males and 834 females) were identified. Meta-analysis indicated that combination medication of pueraria and conventional medicine (CM) was superior to the CM alone in raising left ventricular ejection fraction (LVEF; MD = 6.46, 95% CI, 4.88 to 8.04, P < 0.00001), and decreasing left ventricular end-diastolic diameter (LVEDD; MD = -4.78, 95% CI, -6.55 to -3.01, P < 0.00001), left ventricular end-Systolic diameter (LVESD; MD = -3.98, 95% CI, -5.98 to -1.99, P < 0.00001) and N-terminal pro-brain natriuretic peptide (NT-proBNP; MD = -126.16, 95% CI, -185.30 to -67.03, P < 0.0001). Besides, combination medication improved clinical efficacy rate (RR = 3.42, 95% CI, 2.54 to 4.59, P < 0.00001), 6-min walk test (6-MWT; MD = 65.54, 95% CI, 41.77 to 89.31, P < 0.00001), and TCM syndrome score efficacy (RR = 3.03, 95% CI, 1.57 to 5.83, P = 0.0009). Regarding safety, no difference was observed for adverse events (RR = 0.59, 95% CI, 0.22 to 1.54, P = 0.28). Conclusion The use of pueraria combined with conventional medicine in HFrEF patients has superiority over conventional medicine alone in ameliorating cardiac function and reversing left ventricular remodeling. Moreover, combination medication has no increase in adverse drug events. Given some limitations, more prudence and high-quality clinical trials are needed in the future to verify the conclusions.


Introduction
Heart failure (HF) is a chronic clinical syndrome with high mortality.It is characterized by cardiac dysfunction that results in a decrease in cardiac output and an inability to meet the body's metabolic needs [1].Defined as a global pandemic, there are over 6.5 million people in the United States and an estimated global prevalence of 64.34 million individuals with HF [1][2][3].Despite medical advances, the occurrence of heart failure, specifically heart failure with reduced ejection fraction (HFrEF), has gradually increased over the past 30 years.This has placed a significant burden on healthcare and social systems [3].Left ventricular (LV) remodeling refers to changes in LV structure, which are characterized by changes in LV size, shape, and a reduction in LVEF [4].LV remodeling is the primary pathology of HFrEF occurrence and development, and it is also a key factor that influences the morbidity and mortality of HFrEF [5].Therefore, it prompts clinicians and researchers to explore effective therapies for ameliorating LV remodeling in HFrEF patients.
In China, Chinese herbal medicine (CHM) is widely used as an adjunctive therapy for the treatment of HFrEF, and it has been verified to enhance efficacy and reduce side effects [6,7].Of particular research interest is the herb pueraria (Gegen in Chinese), which has extensive pharmacological actions, including antioxidant stress, anti-inflammation, hepatoprotection, renoprotection, and good cardioprotective effects [8][9][10].Pueraria, sourced from the dried root of Pueraria lobata (Willd.)Ohwi, has been recognized as a homologous medicine and food and is widely used to treat HFrEF in China.It is reported that pueraria and its main bioactive component puerarin can effectively ameliorate cardiac function and reverse LV remodeling [11,12].Currently, there are only a few clinical trials conducted solely on pueraria for HFrEF [13][14][15][16], but there are several trials on CHM compound including pueraria as the main components for HFrEF [17][18][19][20][21][22][23][24][25][26][27][28][29][30][31].These trials indicate that pueraria has exhibited positive therapeutic effects on LV remodeling in HFrEF patients.To date, no systematic studies have been conducted on the impact of pueraria on LV remodeling in HFrEF patients.Based on the available trials, we performed this meta-analysis to thoroughly evaluate the clinical efficacy and adverse drug events of pueraria in treating LV remodeling in HFrEF patients.

Methods
The preferred reporting items for systematic reviews and meta-analysis (PRISMA) were adopted for guiding this study [32].The study protocol was registered on PROSPERO (registration number: CRD42022330748).

Inclusion criteria
Study design.RCTs on pueraria for HFrEF treatment were included, regardless of the publication type.
Interventions.Patients in the experimental group were given a combination treatment of pueraria and controls.Regardless of administration route, various forms of pueraria were considered, including capsules, decoctions, tablets and injection.

Exclusion criteria
The following conditions were employed to exclude studies: 1) study design: reviews, case reports, cell or animal studies, and uncontrolled trials; 2) participants: patients with severe infection, severe heart failure, malignant arrhythmias, hypothyroidism and severe liver and kidney failure; 3) Republished studies (only the most comprehensive data should be selected); 4) Due to incorrect or incomplete data, the meta-analysis cannot be integrated; 5) The full text could not be accessed online or through correspondence with the corresponding author via email.

Data extraction and quality assessment
Endnote 20.5 was used to manage and screen records from databases.Two reviewers independently evaluated the articles based on inclusion and exclusion criteria.The third reviewer resolved any disagreements.Data extraction was simplified by using a standard form, including: 1) study ID (title, first author's name, and publication year), 2) sample size, 3) patient characteristics (age, gender, and NYHA, etc.), 4) intervention details (dose, treatment duration and frequency of administration, etc.), 5) outcomes, adverse reactions, and risk of bias information.Quality assessment was independently carried out by two reviewers using the Cochrane Handbook 5.1 [37].The evaluation mainly including: 1) random sequence generation method; 2) distribution concealment of randomization scheme; 3) blinding; 4) integrity of outcomes; 5) reporting bias; 6) other bias.After that, the bias risk assessment chart drawn was assessed and graphed using Review Manager 5.4.1 software.

Data analysis
Review Manager software (version 5.4.1) was adopted for data analysis.Dichotomous variables were presented as risk ratio (RR), and continuous variables were presented as mean difference (MD).For both variables, 95% confidence intervals (CIs) were calculated.Based on the value of inconsistency index (I 2 ), heterogeneity was statistically assessed and they were displayed in forest plots.A random-effect model was adopted for substantial heterogeneity (I 2 � 50%, or P<0.05);Otherwise, a fixed-effect model was applied.Subgroup analysis of primary outcomes (LVEF, LVEDD, LVESD) was conducted depending on the combinations of pueraria and other herbs.The publication bias was analyzed, and it was reported in a funnel plot.In this study, statistical significance was determined by P value<0.05.
Adverse drug events.Adverse drug events were reported in 10 studies [13-16, 19, 22, 24, 26-28], 4 [13][14][15]28] of which reported no adverse events occurred.7 studies [16,19,22,24,26,27] that included 577 patients reported a total of 6.51% (19/292) adverse events in pueraria combination therapy group and 12.63% (36/285) adverse events in the conventional medicine group.Pueraria combination therapy could cause dizziness, headache, skin rash, astriction, gastrointestinal upset, blood potassium increased, respiratory adverse reactions, and re-hospitalization for patients with HFrEF.Similarly, using conventional medicine alone could cause dizziness, headache, hypotension, skin rash, astriction, arrhythmias, gastrointestinal upset, respiratory adverse reactions, and re-hospitalization.No serious adverse events were reported in both groups.Compared to conventional medicine, pueraria combination therapy was detected without a clear predominance on adverse events (RR = 0.59, 95% CI, 0.22 to 1.54, P = 0.28).Additionally, 1 study [26] reported no statistical difference in re-hospitalization and mortality between the two groups during a 6-month follow-up period.Table 2 provided detailed information.Evaluation of publication bias.Evaluation of publication bias was conducted by comparing 6-MWT.The funnel plot displayed that a slight asymmetry existed, indicating that there appeared to be a slight publication bias among the included studies (Fig 10).We analyzed the sources of publication bias by excluding studies one by one.Nevertheless, this method could not completely eliminate publication bias.Thus, we supposed that publication bias rooted in the fact that all included studies were conducted in China.

Summary of findings
HFrEF remains a major global public health issue and is a leading cause of medical hospital admissions for individuals over the age of 60 [38][39][40].While various medications aimed at improving ventricular remodeling and heart failure have been developed, they have not yielded entirely satisfactory results [41][42][43].Currently, several drugs have been used clinically to treat LV remodeling, including diuretics, beta-blockers, spironolactone, angiotensin receptor blockers (ARBs), and Dagglizin.However, these drugs only marginally improve symptoms, slightly mitigate LV remodeling, modestly prolong the life of HFrEF patients [44].The available drugs for LV remodeling are inadequate to meet current medical needs, and are restricted in their widespread clinical use due to adverse reactions, including dry cough, angioedema, hyperkalemia, low blood pressure, and irreversible kidney failure [45].Due to the adverse events and limited therapeutic effects of western medicine, it is urgent to explore alternative and complementary therapies for ameliorating LV remodeling in HFrEF patients.In our study, it was found that compared with conventional medicine alone, combination therapy of Chinese herbal pueraria and conventional medicine had more benefit for the clinical outcomes of LV remodeling in HFrEF.
The most commonly used monitoring variables for LV remodeling are LVEF, LVEDD, and LVESD [5].In our study, pueraria combination therapy provided superior advantages in ameliorating LV remodeling parameters (LVEF, LVEDD, and LVESD).Subgroup analysis indicated that pueraria combination therapy improved LVEF, regardless of whether puerarin is taken orally or injected.The benefit of pueraria combination therapy in LV remodeling in HFrEF patients was evident regardless of subgroup analysis.This is attributed to pueraria's active components that can reverse ventricular remodeling [12].In addition, we also observed that pueraria combination therapy had betterments in cardiac function (6-MWT and NT-proBNP), clinical efficacy rate, and TCM syndrome score efficacy.
In terms of clinical safety, 6.51% (19/292) of adverse events occurred in pueraria combination therapy group, while 12.63% (36/285) in conventional medicine group.This is attributed to pueraria and its active components that have hepatoprotection and renoprotection [8][9].Due to the fact that only six out of nineteen included studies had reported adverse events (dizziness, headache, hypotension, skin rash, astriction, arrhythmias, gastrointestinal upset, blood potassium increased, respiratory adverse reactions, and re-hospitalization due to cardiac insufficiency) [16,19,22,24,26,27], more studies would be required to validate the safety of pueraria combination therapy in the treatment of HFrEF in future.

Strengths and limitations
This study is the first meta-analysis to evaluate the effect of pueraria on left ventricular remodelling in HFrEF patients.It contributes to guiding clinical medication to ameliorate cardiac function and reverse left ventricular remodeling in HFrEF.By adhering to the PRISMA checklist and Cochrane Handbook, our study draws quantitative conclusions based on scientific and rigorous research.Ultimately, our combined results suggest that pueraria combination therapy can more effectively improve left ventricular remodeling and enhance clinical efficacy in patients with HFrEF.
However, several limitations existed in our review.Firstly, not all of the included RCTs described the allocation concealment and blinding methods.This may have resulted in potential selective bias.Secondly, despite our comprehensive search, all the included RCTs in our study were carried out in China.Thus, the findings may not be generalizable.Thirdly, none of the included RCTs used placebos, which is a potential limitation.Therefore, our findings need to be supported by more well-designed RCTs.Fourthly, most of the included studies did not  describe the follow-up periods, which may have inadequately evaluated the results.Fifthly, due to the included RCTs were conducted between 2000 and 2022, the diagnostic criteria of different periods were inconsistent, which is a possible limitation.Despite these limitations, our manuscript is the first meta-analysis to assess pueraria combination therapy for left ventricular remodeling in HFrEF patients.It will draw great attention from researchers and doctors to the potential benefits of pueraria combination therapy for HFrEF.

Conclusion
According to current evidence, pueraria combined with conventional medicine has superiority over conventional medicine alone in reversing LV remodeling (LVEF, LVEDD, and LVESD), ameliorating cardiac function (6-MWT and NT-proBNP), improving clinical efficacy rate and TCM syndrome score efficacy, as well as good safety in treating HFrEF.However, given some limitations, our conclusion needs to be verified by more high-quality, more prudent clinical studies in the future.

Fig 2
Fig 2 showed the quality assessment result.Only 13 studies[13, 18-20, 22, 24-31]  reported the randomization method and their random sequences were generated by random number

Table 2 . The incidence rate of adverse events. Type Study The number of adverse events Treatment group Control group
https://doi.org/10.1371/journal.pone.0295344.t002